The present invention relates to methods for the treatment of sexual dysfunction in males and females, including but not limited to erectile dysfunction in males.
Impotence or erectile insufficiency is a widespread disorder that is thought to affect about twelve percent of adult men under age forty-five, about twenty percent of men at age sixty, and about fifty-five percent of men at age seventy-five. Similar to male sexual dysfunction, the prevalence of female sexual dysfunction has been shown to increase with age and be associated with the presence of vascular risk factors and the development of menopause.
There is more than one cause of erectile dysfunction. For example, erectile dysfunction can be psychological, resulting from anxiety or depression, with no apparent somatic or organic impairment. Such erectile dysfunction, which is referred to as xe2x80x9cpsychogenicxe2x80x9d, is responsible for about fifteen to twenty percent of cases of impotence. In other cases, the erectile dysfunction is associated with atherosclerosis of the arteries supplying blood to the penis; such dysfunction is referred to as xe2x80x9carteriogenicxe2x80x9d or xe2x80x9catherosclerotic.xe2x80x9d About forty to sixty percent of cases of impotence are arteriogenic in origin.
In still other cases, there is leakage from veins in the penis such that sufficient pressure for an erection can be neither obtained nor maintained. This dysfunction is referred to as xe2x80x9cvenous leakage,xe2x80x9d or xe2x80x9cabnormal drainagexe2x80x9d. This condition is often exacerbated by the presence of some arteriogenic dysfunction whereby the supply of blood to the penis is impaired. In still other cases, the dysfunction is associated with a neuropathy, such as nerve damage arising from, for example, surgery or a pelvic injury, in the nervous system affecting the penis. Such a dysfunction is referred to as xe2x80x9cneurogenicxe2x80x9d and this accounts for about ten to fifteen percent of cases of impotence.
There is also a high incidence of erectile insufficiency among diabetics, particularly those with insulin-dependent diabetes mellitus. Erectile dysfunction in diabetics is often classified as xe2x80x9cdiabetogenic,xe2x80x9d although the underlying dysfunction is usually neurogenic associated with neuropathy, but may be arteriogenic or neurogenic and arteriogenic. About half of diabetic males suffer from erectile insufficiency, and about half of the cases of neurogenic impotence are in diabetics.
Additionally, erectile insufficiency is sometimes a side effect of certain drugs, such as beta-blockers that are administered to reduce blood pressure in persons suffering from hypertension, or drugs administered to treat depression or anxiety. Excessive alcohol consumption has also been linked to erectile insufficiency. These forms of erectile insufficiency may be regarded as a subset of neurogenic or psychogenic insufficiency.
Determination whether a human male is suffering from impotence that is substantially only neurogenic or psychogenic is readily made by a person skilled in the art using a number of readily available diagnostic procedures. Thus, a male suffering from impotence can first be given a physical examination with particular attention to possible penile and scrotal pathology, whereby any anatomical deficiency precluding an erection sufficient for vaginal penetration can be detected. In the absence of such an anatomical deficiency, the male can be subjected to tests, whereby penile venous leakage or severe or untreatable atherosclerosis can be detected.
Such tests include determination of the penobrachial blood pressure index (PBPI), doppler investigation of the penile arteries, and a papaverine test. The PBPI is the penile systolic blood pressure divided by the systolic blood pressure determined at one of the arms. These blood pressures can be determined by any number of standard techniques. Thus, the penile systolic blood pressure can be determined by (i) placing an inflatable cuff around the base of the free part of the penis in the flaccid state which is capable of being used to apply variable pressure, readable from a gauge, to an object around which the cuff is placed, (ii) localizing the penile arteries with a Doppler ultrasound probe (e.g., 8 MHz probe, such as the Mini Doplex D500 available from Huntleigh Technology, Luton, United Kingdom), and then (iii) inflating and deflating the cuff and ascertaining the pressure at which the Doppler sound reappears.
The pressure at which the Doppler sound reappears is the penile systolic blood pressure. A male""s penile blood pressure is regarded as normal if his PBPI is  greater than 0.80. With regard to Doppler investigation, each of the two penile cavernous arteries is investigated distal to the aforementioned cuff using the Doppler ultrasound problem. The function of each of the two arteries is assessed by Doppler ultrasound using an arbitrary scale of 0, 1, 2 or 3, where 0 means that the function is so deficient that the artery cannot be located and 3 means that the artery is well enough that maximal Doppler sound is observed.
In the papaverine test, a tourniquet is placed at the base of the free part of the penis and tightened and then, with the patient seated, 30 mg of papaverine in 1 ml of a physiological acceptable fluid (e.g., physiological saline or phosphate-buffered saline) is injected into the penile cavernous body. In persons suspected of having impotence due to a suprasacral nerve lesion or a psychogenic dysfunction, only 15 mg of papaverine is administered, because of the high incidence of papaverine-induced priapism in such cases.
Five minutes after the injection, the tourniquet is removed and an ultrasound Doppler investigation of the penile cavernous arteries is carried out as described above. The function of the arteries is regarded as normal if both of them score a 3 on the arbitrary scale. After the Doppler investigation, penile vibration, at about a 4 Hz with an amplitude of about 1.2 mm (carried out with, e.g., a Vibrector from Multicept, Gentofte, Denmark) is carried out for five to ten minutes and then erectile response is evaluated.
Erectile response is classified as full rigidity, if the angle between the penis and the legs in the standing position is  greater than 90xc2x0, and tumescence or no response if the angle is less than or equal to 45xc2x0. An impotent male, who does not have an anatomical deficiency that would preclude having an erection sufficient for vaginal penetration, who has a PBPI greater than 0.80, who has scores of 2 or 3 in Doppler ultrasound investigations of both of the cavernous arteries of the penis, after papaverine injection and vibration as described above, is suffering from impotence that is xe2x80x9csubstantially only neurogenic or psychogenicxe2x80x9d in origin.
It is possible that atherosclerosis or venous leakage contributes to such impotence, and atherosclerosis likely does contribute if the score is less than 3 in the Doppler investigation of one or both of the cavernous arteries after papaverine injection; but any venous leakage or atherosclerosis in such impotence is not untreatable and, consequently, is not a substantial factor in the impotence and such atherosclerosis, if any, is less than severe.
Impotence, which is a side-effect of drugs such as beta-blockers, is deemed to be neurogenic impotence in the present specification. Similarly, impotence which is a result of alcoholism or excessive consumption of alcohol, is deemed to be neurogenic or psychogenic impotence, for purposes of the present specification. Thus, a male who is diagnosed in accordance with the present specification as suffering from impotence that is xe2x80x9csubstantially only neurogenic or psychogenicxe2x80x9d in origin is suffering from impotence that is substantially only neurogenic, psychogenic or neurogenic and psychogenic in origin, even though an underlying cause of the impotence has been identified as a side-effect of a drug, alcoholism or excessive consumption of alcohol.
Generally, a male with a PBPI less than about 0.60, with scores of 0 in Doppler investigations of both penile cavernous arteries (after papaverine injection as described above), and with a less than fully rigid erection after papaverine injection and vibration will have impotence caused by xe2x80x9cuntreatablexe2x80x9d atherosclerosis. Methods are available to ascertain whether impotence is untreatable because of venous leakage.
One method of ascertaining whether untreatable venous leakage is a cause of impotence is by cavernosometry, optionally supplemented with cavernosography. See, e.g., Delcour et al., Radiology 161: 799 (1986); Porst et al., J. Urol. 137: 1163 (1987); Lue et al., J. Urol. 37: 829 (1987). Cavernosometry can be done using, both before and after intracavernosal injection of 60 mg of papaverine (in 1 ml of physiological saline), infusion of physiological saline through a 19-gauge needle into one corpus cavernosum with a 21-gauge needle inserted into the other corpus cavernosum for measurement of intracorporal pressure (which is recorded on a plotter).
The infusion rates needed to induce and maintain an erection are measured. If the infusion rate needed to maintain an erection is greater than 50 ml/min before administration of the papaverine and greater than 15 ml/min after administration of the papaverine, untreatable venous leakage is present. As long as an erection can be achieved at some flow rate less than about 100 ml/min before injection of the papaverine and less than about 50 ml/min after the injection of papaverine, it might be possible, using cavernosography, to locate the venous lesion associated with the leakage, and thereby confirm the diagnosis based on cavernosometry and provide information for possible surgical correction for the leakage. In the cavernosography, the penis is X-rayed, both before and after intracavernosal injection of 60 mg papaverine (in 1 ml of physiological saline), while infusing contrast medium into the corpus cavernosum (e.g., through a 19-gauge needle) at a flow rate that maintains an erection during the x-raying. Numerous contrast media suitable for the procedure are available in the art; these are typically aqueous solutions of iodinated compounds that provide between about 180 mg/ml and about 360 mg/ml of iodine. Examples are a solution of iohexol providing 240 mg/ml of iodine sold by Winthrop Pharmaceuticals, New York, N.Y., USA, and a solution of iopamidol providing 300 mg/ml iodine sold by Astra Meditec, Goteborg, Sweden. Typically 50-100 ml of the contrast medium will be employed for each x-ray (i.e., before and then after the injection of papaverine). In the cavernosometry and cavernosography, 30 mg papaverine (in 1 ml physiological saline) coupled with stimulation by vibration can be employed in place of 60 mg papaverine (in 1 ml physiological saline).
A number of methods to treat impotence are available. These treatments include pharmacological treatments, surgery and, in cases of psychogenic dysfunction, psychological counseling is sometimes effective. Psychogenic impotence often can be cured by counseling coupled with a demonstration to the patient that he is capable of having a full erection by inducing such an erection once or a few times in the patients. Insufficiency due to excessive alcohol consumption is sometimes cured by reducing or elimination such consumption.
In the rare cases, where the insufficiency is physical because of venous leakage, surgery can usually be employed to repair the venous lesion and thereby either cure the insufficiency or, if there remains an erectile insufficiency after repair of the venous lesion, render the insufficiency amenable to treatment by pharmacological methods. Also, penile implants, which provide a mechanical means to produce an erection sufficient for vaginal penetration, are widely used to treat impotence. In recent years, implants have been employed, especially in cases where pharmacological intervention is ineffective, which are usually cases of severe atherogenic impotence. Treatment of impotence with penile implants, however, entails serious disadvantages. Such treatment requires surgery and necessitates total destruction of the erectile tissues of the penis, forever precluding normal erection.
Pharmacological methods of treatment are also available. Such methods, however, have not proven to be highly satisfactory and can be accompanied by severe side-effects. Papaverine is now widely used to treat impotence, although papaverine is ineffective in overcoming impotence due, at least in part, to severe atherosclerosis. Papaverine is effective in cases where the dysfunction is psychogenic or neurogenic and severe atherosclerosis is not involved. Injection of papaverine, a smooth muscle relaxant, or phenoxybenzamine, a non-specific blocker and hypotensive, into a corpus cavernosum has been found to cause an erection sufficient for vaginal penetration. Also, in cases where severe atherosclerosis is not a cause of the dysfunction, intracavernosal injection of phentolamine, an xcex1-adrenergic blocker, causes an erection sufficient for vaginal penetration. The resulting erection is one of significantly shorter duration than that induced by intracavernosal injection of papaverine or phenoxybenzamine and is of such short duration that satisfactory sexual relations are difficult or impossible.
Treatment of impotence with papaverine or phenoxybenzamine often results in priapism, a locking-up of an erection for a long period of time, typically a few hours and sometimes longer than twenty-four hours. Priapism is a serious, deleterious side effect of treatment of erectile insufficiency with these drugs. Beyond the embarrassment that may be caused for some men, priapism is usually painful, irreversibly damages erectile tissue, and, to be relieved, requires bleeding or pharmacological intervention, such as injection of a sympathomimetic drug, such as adrenaline.
Even if priapism does not occur with use of papaverine, such use is associated with a painful, burning sensation in the first two or so minutes after the injection and there are indications that repeated use of papaverine causes undesirable, extensive intracavernous fibrosis. Further, as indicated above, impotence arising from severe atherosclerosis is not susceptible to treatment with papaverine, phenoxybenzamine, phentolamine or papaverine together with phentolamine. In any case, phenoxybenzamine is not suitable for use in treating impotence because it is a carcinogen.
Thus, although impotence is a ubiquitous problem, there are few satisfactory methods available for treating this disorder. Because of the relatively invasive intervention involved and the high failure rate of penile prostheses, surgical approaches provide unattractive alternatives. A safe pharmacological approach to the treatment of impotence is still to be achieved.
In humans, penile erection is dependent upon the relaxation of the smooth muscle tone in cells of the corpus cavernosum. This relaxation is dependent on the presence of adequate levels of a cyclic guanosine monophosphate (cyclic GMP) and cyclic adenosine monophosphate (cyclic AMP), which are regulated by phosphodiesterase (PDE) isoenzymes. Cyclic GMP and cyclic AMP are secondary messengers that can be degraded by PDE isoenzymes. The second messenger signal pathway is essential for cavernous smooth muscle relaxation.
There are seven known types of phosphodiesterase isoenzymes which, if inhibited, affect different functions of the body. For Example, type I phosphodiesterase (PDE I), if inhibited, affects among others the human cardiac ventricle; type IV phosphodiesterase (PDE IV), if inhibited, affects among other organs and tissue, the human skeletal muscle; while type VI phosphodiesterase (PDE VI), if inhibited, affects the human retna. Joint Clinical Review, page 4, Jan. 22, 1998. Types III and V phosphodiesterase (PDE III and PDE V, respectively), if inhibited, are known to affect, among other organs and tissue, the human corpus cavernosum. Stief et al, J. Urol. 159(4): 1390-3 (1998). For example, the hydrolysis of the second messenger cyclic AMP by PDE III is known to play an important regulatory role in the relaxation of cavernous smooth muscle of the penis. Kuthe et al., Chem. Biol. Interact. 119-120: 593-8 (1999). On the other hand, Sildenafil, commonly known as Viagra(copyright), is a selective PDE V inhibitor. Sildenafil selectively increases cyclic GMP levels in coronary vascular smooth muscle tissue, but produces no change in cyclic AMP levels. Sildenafil exhibits negligible inhibition of PDE III. Wallis et al., Am. J. Cardiol. 83 (5A): 3C-12C (1999).
Applicant has discovered compounds, that are selective PDE III inhibitors and that are useful in the treatment of sexual dysfunction in both males and females. Moreover, the compounds minimize the undesirable side effects associated with papaverine, phenoxybenzamine, and phentolamine. Papaverine, for example, is a non-selective inhibitor of PDE, i.e., papaverine will inhibit all types of phosphodiesterase, not just PDE III. Accordingly, using a selective inhibitor specific to PDE III which affects the human corpus cavernosum in the treatment of patients with sexual dysfunction would have a beneficial therapeutic effect.
It is an object of the present invention to provide a method for treating sexual dysfunction in males and females with inhibitor compounds that are selective for inhibiting PDE III.
It is a further object of the invention to provide for a method of treating sexual dysfunction in males and females, in particular, male erectile dysfunction with quinolines, isoquinolines and quinolones, including derivatives thereof, which are PDE III inhibitors.
It is still a further object of the invention to provide a method for using thioquinolone or sulphinyl or suphonyl derivatives, PDE III inhibitors, to treat sexual dysfunction in males and females, in particular, male erectile dysfunction.
It is still a further object of the invention to use flosequinan (7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone), a PDE III inhibitor, to treat sexual dysfunction in males and females, in particular, male erectile dysfunction.
It is still a further object of the invention to use a 2-oxoquinoline and derivatives thereof, PDE III inhibitors, to treat sexual dysfunction in males and females.
It is still a further object of the invention to treat sexual dysfunction in both males and females with cilostazol (6-[4-(1-cyclohexyl-5-tetrazoyl)butoxy]-1,2,3,4-tetrahydro-2-oxoquinoline), also known as 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)-butoxy]-3,4-dihydro2(1H)-quinoli-none and 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril.
It is still a further object of the invention to treat sexual dysfunction in both males and females with metabolites of cilostazol, in particular, monohydroxycilostazol, monohydroxy- dehydrocilostazol, 3,4-dihydro-6-hydroxy-2(1H)-quinolone, their conjugates and dehydro-cilostazol.
It is still a further object of the invention to coat the interior of a condom with the selective PDE III inhibitors of the invention to induce erection.
Definitions
As used herein, the term xe2x80x9cquinolinexe2x80x9d refers to chemical compositions comprising quinoline as set forth in the following structure: 
as well as other forms of quinoline such as isoquinoline: 
and 2-oxoquinoline: 
As used herein, the phrase xe2x80x9cderivatives of quinolinexe2x80x9d refers to chemical compositions comprising quinoline with a chemical group attached, including halogenated quinoline, e.g., 5-bromoquinoline: 
and 1-methylisoquinoline: 
As used herein, the phrase xe2x80x9cmethylsulphinyl derivatives of quinolinexe2x80x9d refers to chemical compositions comprising quinoline with a methylsulphinyl group attached. Examples include flosequinan (7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone): 
and sulfone metabolites of flosequinan: 
As used herein, xe2x80x9ccilostazolxe2x80x9d refers to a chemical compound as set forth in the following structure: 
As used herein, a patient who is xe2x80x9cfree from cardiac diseasexe2x80x9d and a patient who is xe2x80x9cfree from symptoms of cardiac diseasexe2x80x9d indicate that the patient has not been diagnosed with angina, myocardial infarction, congestive heart failure and that symptoms of angina, ischemia, myocardial infarction, congestive heart failure have not been detected, respectively.
As used herein, xe2x80x9cdrugs that have hypotensive effectsxe2x80x9d are those drugs which, when administered, cause the patient""s end-diastolic blood pressure to be reduced. Nitrates are commonly used drugs which have hypotensive effects.
As used herein, xe2x80x9cnitratesxe2x80x9d are compounds that contain the xe2x80x94NO3xe2x80x94 moiety. Nitrates typically used in the clinic are shown in Table 1.
As used herein, xe2x80x9cnitritesxe2x80x9d are compounds that contain the xe2x80x94NO2xe2x80x94 moiety. Nitrites typically used in the clinic are shown in Table 1.
As used herein, xe2x80x9ccorpus cavernosumxe2x80x9d means the columns of erectile tissue forming the body of the clitoris (c. cavernosum clitoridis) or the penis (c. cavernosum penis).
As used herein, the term xe2x80x9cerectile dysfunctionxe2x80x9d refers to certain disorders of the cavernous tissue of the penis and the associated facia which produce impotence, i.e., the inability to attain a sexually functional erection.
As used herein xe2x80x9ccondomxe2x80x9d refers to a sheath or cover to be worn over the penis in coitus to prevent impregnation or infection.
As used herein xe2x80x9cstandard injectionxe2x80x9d refers to the placement of a pharmaceutical composition into a subject with a hypodermic needle. For example, such injection can be made subcutaneously, intravenously, intramuscularly and intracavernosally.
As used herein, xe2x80x9cintracavernosalxe2x80x9d injection is injection into the corpus cavernosum of the penis.
As used herein, an xe2x80x9cerectionxe2x80x9d refers to the condition of a penis whereby it is at least semi-rigid as opposed to being in a flaccid state.
As used herein, xe2x80x9cby oral administrationxe2x80x9d refers to the introduction of a pharmaceutical composition into a subject by way of the oral cavity in aqueous liquid or solid form.
As used herein, xe2x80x9ccutaneouslyxe2x80x9d refers to the introduction of a pharmaceutical composition into a subject by application to the surface of the skin such that the composition is absorbed into the subject.
As used herein, xe2x80x9ctransurethrallyxe2x80x9d refers to the introduction of a pharmaceutical composition to the urethra of a subject such that the composition is absorbed into the subject.
As used herein, xe2x80x9csufficient for vaginal penetrationxe2x80x9d refers to the state of an erection such that the penis is capable of entering a vagina without manual manipulation.
As used herein, xe2x80x9csexual stimulationxe2x80x9d refers to activity that would induce an erection in a male without erectile dysfunction such as sexually explicit media, manual manipulation, vibration, or live erotic entertainment.
As used herein, xe2x80x9csexually explicit mediaxe2x80x9d refers to films, videos, books, magazines or photographs that depict sexual activity.
As used herein xe2x80x9csingle dosagexe2x80x9d refers to a pharmaceutical composition of a formulation that is capable of achieving its intended effect in a single application.